Non-surgical therapy for the treatment of chronic low back pain in patients with Modic changes: A systematic review of the literature

Background In absence of uniform therapeutic recommendations, knowledge of the available treatment options for Modic changes (MCs) patients and their safety and effectiveness would be crucial and significant for clinicians and such patients. Objectives The aim of this study was to provide a systematic review of available studies on non-surgical treatments of MCs. Methods We performed a systematic review of multiple electronic databases including PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure for the period until 31st August 2021 to search for studies on non-surgical treatments for MCs in accordance with the guidance of the Cochrane Handbook. Potential studies were screened by their titles and abstracts. The methodological quality of the included studies was independently evaluated by two authors. Final recommendations for the included interventions were developed based on grades of recommendations. The narrative format was adopted to synthesize the findings of the present work. Results Fifth studies involving a total of 1147 patients were identified for this systematic review. The results of this review demonstrated that spinal manipulation has been suggested as an alternative option for patients with MCs. However, there was insufficient evidence to support that patients with MCs can benefit from the medication and wearing the rigid lumbar brace. Moreover, the rationale and safety for the use of antibiotics in such patients remain highly controversial. Low evidence revealed that exercise therapy might decrease pain intensity only for special subgroups of MCs patients. Conclusions There is not yet enough evidence to suggest that non-surgical treatments are useful for patients with MCs. Further high-quality, multicenter trials are required to validate the effectiveness of these non-surgical treatments.


Introduction
Chronic low back pain (CLBP) is the leading health condition afflicting most of population in the context of population increases and ageing [1]. Due to its high rate of disability and health insurance use, CLBP has become a common disabling condition with adverse consequences worldwide [2,3]. It has been reported that more than 80% of individuals will experience CLBP at least once at some point in their lifetime [4]. Therefore, CLBP exerts essential impacts not only on the individual but also adversely affects communities and health care systems [5].
It still remains unknown or uncertain about the etiology and pathomechanisms of CLBP. Osteoarthritis of the spine is widespread, with an estimated prevalence ranging from 40-85% [6]. Several studies [7,8] have reported the relationship between CLBP and osteoarthritis degeneration of spine. Facet joint osteoarthritis itself has adequate nerve supply capable of leading low back pain [7]. The commonly accepted viewpoint in academia is that disc degeneration [9], facet joint arthrosis, and sacroiliac joint arthrosis [10] are the common causes of CLBP [11]. However, multiple conditions can affect facet and sacroiliac joint arthrosis, resulting in low back pain deriving from osteoarthritis degeneration of spine [11]. Moreover, osteoarthritis is the clinical outcome of a disease process that has been characterized by damage to articular cartilage, subchondral bone alteration, and a synovial inflammatory response [12], which may be strongly linked to the development of Modic changes (MCs) [8].
Signal intensity changes in the subchondral bone marrow adjacent to the vertebral endplate visible on magnetic imaging resonance (MRI), also known as MCs, have been the research hot on their clinical features and pathomechanisms. The histological manifestations and classifications of MCs were preliminarily elaborated by Modic et al. [13,14] in 1988. It, coupled with their more severe radiographic performance than simple disc degeneration [15,16] and positive correlation with CLBP [17], has also been attracted widespread academic attention. Although a recent paper from the Wakahama Spine Study [17], have reported a positive association between MCs and LBP, the most recent systematic review on this topic [18] concludes that the associations between MCs and LBP-related outcomes are inconsistent. Meanwhile, there are still no uniform therapeutic recommendations for MCs patients, and the establishment of treatment regimens depends primarily on the patient's symptoms (mainly CLBP). Therefore, non-surgical treatments such as physical therapy or medication are often recommended as the first-line treatment option for CLBP in clinical guidelines [19]. However, when the patient does not respond well to non-surgical treatments, then surgery should be considered.
Currently, a variety of non-surgical interventions targeting potential etiology and pathogenesis of MCs have been successively reported. However, the evidence on which non-surgical treatments are effective and safe for patients with MCs is inconclusive. The purpose of the present work was therefore to systematically review currently available studies on non-surgical treatments of MCs patients, with the aim of being able to find valuable evidence for treating such patients.

Materials and methods
This systematic review was carried out in strict accordance with the standard methodology of the Cochrane Handbook. The results of the study were reported under the guidance of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) proposed by the PRISMA Working Group [20]. The protocol of this review was registered with PROSPERO (registration number CRD42021272154). The present work is a secondary analysis of published studies on a specific topic. Therefore, ethics committee approval is not necessary for this study.

Search strategy
In the absence of international guidelines for the management of MCs, different therapeutic strategies have been described. It is therefore difficult to generalize these treatment options using several specific search terms. To perform a comprehensive search, it was decided after discussion in the research group to use the following search terms: "Modic changes", "endplate signal changes", "endplate bone marrow lesions", "active discopathy". Two reviewers with at least 3-year experience in literature retrieval independently searched electronic databases of Medline via PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure for the period until 31 st March 2022. Literature search strategy using PubMed database as an example is shown in File 1. No language limitation was settled for inclusion in the present work. We also manually searched the references of the included studies and relevant reviews to identify potential studies that were not retrieved in the preliminary search.

Eligibility criteria
We developed the inclusion criteria for this systematic review based on the PICOs (population, intervention/exposure, comparison/control, outcome, and study design) principles of clinical interventional study: 1) Population: adult patients (age !18-year met the diagnostic criteria for CLBP (>6 months' duration) [21] and had the evidence of MCs on lumbar MRI. The studies that included cases with a history of prior lumbar surgery would not be considered to include in the present work.  2) Intervention: medication and physical therapy. 3) Comparison: placebo, the standard of care, observation-only, or none. 4) Outcomes: any clinical outcomes including but not limited to pain intensity, disability, quality-of-life measures, the volume of MCs, or adverse events. 5) Study design: randomized controlled trial (RCT), observational cohort (single or double arms), or case series. In this systematic review, we only included the one with the most complete outcome indicators for multiple papers from the same study. Review, animal experiment, case report, comment, and conference report were excluded. Moreover, the present work also excluded studies that did report results for a group of patients where some but not all had MCs, and for studies with interventions not specifically meant to target patients with MCs but where some had MCs.

Study selection
The retrieved records were all imported into EndNote, a world's essential reference management tool. Duplicate records from multiple databases were consolidated and then automatically eliminated. The titles and abstracts of the literature were independently browsed by two authors, marking these as included, excluded, or inconclusive. Studies marked as exclusion by both authors were preliminarily removed. Full texts of eligible and inconclusive studies were then downloaded and reviewed independently. The disagreement between authors was resolved by the consensus among researchers.

Data extraction
A standardized form was designed to summarize the characteristics and results of each included study. Information from the included studies was independently extracted by two authors and filled into the form. A third author was employed to check information in two forms from the above-mentioned authors. If necessary, the authors of the included studies were contacted by email for additional information about their studies. The following data items were extracted: 1) study characteristics: authors information, publication year, study design and place, follow-up, and population; 2) interventions: number of each group, and specific treatment options (dosage, duration); 3) outcomes measures and adverse events.

Risk of bias assessment
Two authors independently assessed the methodological quality of the included studies, and a third author was introduced to resolve disputes between the two authors. We adopted the bias risk tool (Table 1a) proposed by the Cochrane back review group to assess the risk of bias of the included RCTs [22], the Newcastle-Ottawa Quality Assessment Scale (NOQAS) [23] to evaluate the quality of the included comparative studies (Table 1b), and the evidence-based guideline development methodology of the North American Spine Society (NASS) to assess the level of evidence of the included case series (Table 1c).
Grades of recommendations for summaries or reviews of studies were used to assess the cumulative body of evidence for all identified interventions ( Table 2). The strength of evidence across the studies was considered as one of the following four categories: good (mark as A), fair (B), poor (C), and insufficient or conflicting evidence (I).

Literature search
A flow chart of the literature retrieval process based on the PRISMA statement is presented in Figure 1. Our initial electronic search identified 2143 documents that potentially met the inclusion criteria under the established search strategy. After integration by EndNote software, 795 duplicated studies were excluded. Then, we eliminated 1348 irrelevant   studies after a careful review of the titles and abstracts. The full texts of the remaining 54 papers were read, and the final 15 studies [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38] that fully met the inclusion criteria were included in this systematic review.

Study characteristics and risk of bias
This systematic review included a total of 1147 patients in 15 studies involving a variety of non-surgical treatments. Nine studies targeted on the effects of medications on the patients with MCs, including antibiotics [26,31,32], glucosamine sulfate [33], zoledronic acid [27,34,35], calcitonin [36], and probiotics [37]. Additionally, 5 studies focused on the efficacy of spinal manipulation [28,29], rigid lumbar brace [30] and exercise therapy [24,25] in patients with MCs. The remaining one study [38] adopted a combination of physical therapy and medication. The characteristics and main findings of the included studies were summarized in Tables 3 and 4, respectively.
Of these 15 studies, nine studies [24,25,27,31,32,33,34,35,37] were RCTs and the risk of bias results are shown in Table 5. Most RCTs addressed "YES" for adequate the method of randomization (9/9,100%), Two or more consistent Level IV studies. I There is insufficient or conflicting evidence not allowing a recommendation for or against intervention.
Insufficient evidence to make recommendation for or against.
A single level I, II, III or IV study without other supporting evidence.
More than one study with inconsistent findings*.
* Note that in the presence of multiple consistent studies and a single outlying, inconsistent study, the Grade of Recommendation will be based on the level of the consistent studies.  treatment allocation concealed (8/9, 88.9%), patient blinded to intervention (9/9,100%), outcome assessor blinded to intervention (9/9, 100%), drop-out rate described and acceptable (8/9, 88.9%), all randomized participants analyzed in the allocated group (8/9, 88.9%), groups similar at baseline (9/9,100%), cointerventions avoided or similar (8/9, 88.9%), and timing of the outcome assessment similar (9/9, 100%). However, a high proportion addressed "UNSURE" for care provider blinded to intervention (6/9, 66.7%), free of suggestion of selective outcome reporting (8/9, 88.9%), compliance acceptable in all groups (7/9, 77.8%), and other sources of potential bias (5/9, 55.6%). Four studies [26,28,29,30] were case series and their methodological qualities were considered as grade IV. The other 2 studies [36,38] were observational cohort studies and were rated as high quality according to NOQAS with a quality score of more than 6 points. Grades of recommendations for various treatments of MCs are summarized in Table 6. In the rest group, 49 patients were educated to avoid heavy physical activity and to rest by lying down twice a day for one hour each time. In addition, these patients were also given a flexible belt and instructed to use it for up to four hours a day as required. The remaining 51 patients received exercises for muscle stabilization in the lower back and    abdominal together with additional training for postural instability and light physical fitness in a group of up to a maximum of 10 patients under the guidance of a physiotherapist for one hour per week for 10 weeks. These patients were also encouraged to do the same training at home three times a week. Finally, 78 patients completed the full treatment program with a 22% of dropout rate. In their study published in 2012 [24], no differences were detected in pain, disability, general health, depression, and globe assessment between the two interventions. At the 1-year follow-up, the number of patients seeking additional treatments was 30 (64%) in the rest group while 23 (50%) in the exercise group, without statistical difference. Additionally, there was no significant difference in the increase of pain intensity between the rest (3 cases) and exercise (5 cases) groups.
However, Jensen et al. [25] conducted a secondary subgroup analysis of the above patients in 2015 and found that patients with Modic type 1 change (MC1) were 0.17 points worse in low back pain intensity at rest than exercise (0.17; 95% CI -1.28 to 0.93), those with larger MCs were 0.41 points worse at rest than exercise (0.41; 95% CI -1.62 to 0.79), and those with large MC1 were 0.61 points worse at rest than exercise (0.61; 95% CI -1.82 to 0.61). Interestingly, this result is contrary to their previous hypothesis that "patients with these MRI findings would benefit more from rest than from exercise therapy".

Rigid lumbar brace
To our best knowledge, only one single-arm observational cohort [30] reported the efficacy of custom-made rigid lumbar brace for the treatment of patients with MC1. Sixty-two CLBP patients with MC1 were asked to wear a custom-made lumbar rigid brace every day (except lying down) for 3 months based on no change in their daily activities. At the final follow-up, the number of patients with pain improvement of at least 30% and 50% was 49 cases and 39 cases respectively, and the mean improvement percentage after 3 months of brace wearing was 49%. However, despite no adverse events, almost all patients experienced a recurrence of pain two months after brace withdrawal.

Spinal manipulation
Two articles by Annen et al. published in 2016 [28] and 2018 [29] were the only two studies that could be retrieved on the efficacy of manipulation in the treatment of patients with CLBP combined with MCs. Both studies used high-velocity, low-amplitude spinal manipulation. The major difference was whether the study subjects had the combined lumbar disc herniation.
A study [28] published in 2016 mainly focused on patients with MCs with lumbar disc herniation. They found that the manipulation therapy had a good short-term effect on CLBP patients with or without MCs. However, the clinical improvement in 76.5% of Modic positive patients and 53.3% of Modic negative patients at 2 weeks, indicated that patients with MCs can benefit more from the manipulation therapy. Moreover, patients with MCs had a larger decrease in the level of disability at 3 and 6 months. And patients with Modic type 2 change (MC2) responded more positively and effectively to the manipulation compared to patients with MC1 (p ¼ 0.001) at 1-year follow-up.
In their subsequent study [29], MCs patients without lumbar disc herniation were employed as study subjects. The result that manipulation therapy was effective in treating CLBP patients with MCs was once again reported. However, there were no significant differences in clinical improvement between Modic positive and negative patients or between MC1 and MC2 patients. Therefore, they concluded that the presence or absence of MCs and the MCs types might be not related to treatment outcomes for MCs patients without disc herniation who underwent chiropractic care.

Antibiotics
Three studies [26,31,32] reported on the safety and efficacy of antibiotics for the treatment of CLBP combined with MCs, two of which were RCTs [31,32] and another was a single-arm prospective study [26].
In 2008, Albert et al. [26] conducted a prospective study of 32 patients with MCs to first explore the effects of antibiotics on the MCs at the end of Amoxicillin-clavulanate treatment (90 days) and 11-month post-treatment. All clinical indicators improved statistically at follow-up points in the remaining 29 patients, except for 3 patients who withdrew from the study due to severe diarrhea (p < 0.001). The authors, therefore, concluded that this result could provide favorable evidence for the hypothesis of bacterial infection in MCs. Subsequently, they conducted another randomized double-blind trial of 162 CLBP patients with MC1 for a 1-year follow-up [31]. In this study, patients in the antibiotic group received amoxicillin-clavulanate tablets (500mg/125mg) three times a day, 1 or 2 tablets each time, for 100 days. All outcome measures were significantly improved in the antibiotic group and continued to be so at the one-year follow-up. Moreover, there were statistically significant improvements on decreasing the sizes of MCs and clinically important in terms of the relative magnitude of improvement for the primary outcome measures as well as decreasing the sizes of MCs compared to the placebo group. In addition, there was a positive trend towards a dose-response relationship and double-dose antibiotics appeared to be more effective. However, the high rate of adverse events associated with antibiotic treatment was also noted by the authors in the article as such (65% in the antibiotics group vs 23% in the placebo group).
The above conclusions have been overturned by a recent study [32]. In this study, 180 patients with MC1 or MC2 with lumbar disc herniation were randomized to receive oral treatment with either 750 mg amoxicillin or a placebo three times daily for three months. However, these patients did not have significant clinical improvement after three months of amoxicillin treatment compared with the placebo group. Therefore, this study did not support the use of antibiotics in patients with MCs.

Glucosamine sulfate (GS)
Wilkens et al. [33] selected specific subjects from their previous study for subgroup analysis to investigate the effects of GS in the treatment of MCs. 42 patients who completely met the inclusion criteria randomly received GS or placebo 1500mg every day for 6 months. At the treatment endpoint, radiographic parameters revealed that there were no significant differences in proportions of MCs with increased MC1-dominance (OR placebo: GS 2.4, 95% CI 0.6-9.7; p ¼ 0.22), or decreased MC1-dominance (OR GS: placebo 1.6, 95% CI 0.4-6.1; p ¼ 0.46), or increased MC size (OR 1.0, 95% CI 0.2-4.7; p ¼ 0.97). Therefore, the authors concluded that GS has no clear efficacy in CLBP patients with MCs.

Zoledronic acid (ZA)
Three RCTs [27,34,35] aimed at investigating the efficacy of ZA in CLBP patients with MCs were included in this systematic review. Two [34,35] of 3 studies were from a research team and targeted the same subjects, but different indicators were employed to evaluate clinical outcomes after treatments. Forty patients with MCs were divided into two groups to receive either an intravenous infusion of 100 ml saline dissolved in 5 mg ZA (20 patients) or 100 ml of saline as a placebo (20 patients). The remaining one study [27] that included 25 patients with CLBP and MCs (ZA: 13 cases and placebo: 12 cases) was to assess the efficacy of oral 50 mg ZA once a week for 6 weeks.
In 2014, Koivisto et al. [34] reported that patients receiving an intravenous infusion of ZA could obtain a significant benefit in reducing intensity of CLBP at 1 month of treatment (MD 1.4; 95% CI 0.01 to 2.9). However, there were no significant differences in improving the oswestry disability index (ODI) and decreasing CLBP intensity at 1 year of follow-up between ZA and placebo group. Additionally, more mild adverse events that do not require clinical management were observed in the ZA group (ZA: 19/20; placebo: 7/20). In the subsequent study [35], they found that the intensity of CLBP was positively associated with existing MC1, and ZA had a significant effect in reducing the volume of MC1 than placebo (ZA: À0.83 cm 3 , decrease vs placebo: 0.91 cm 3 , increase). However, no significant difference in decreasing the volume of MC2 between both groups was detected (ZA: 2.40 cm 3 , increase vs placebo:1.97 cm 3 , increase). A recent study from Shea et al. [27] has also reached to the similar findings. Patients with oral 50 mg ZA once a week for 6 weeks have significant reduction in MC endplate affected area at 6-month follow-up compared to placebo (p ¼ 0.041). Moreover, subscale RAND-36 metrics for physical function (p ¼ 0.038), energy/fatigue (p ¼ 0.040) and pain (p ¼ 0.003) in the ZA group were improved at 3-months compared to placebo, with significant differences in pain intensity at 4-weeks and 6-months.

Calcitonin
In recent, a study [36] evaluated the efficacy of calcitonin and diclofenac sodium in CLBP patients with MC1. In this retrospective study, 62 patients were injected intramuscularly with calcitonin 50 IU once daily and 47 patients were treated with diclofenac 75 mg once per day for 4 weeks. Compared with baseline, there were significant improvements in visual analogue scale (VAS) and ODI scores at 4-week and 3-month after treatment in both groups (P < 0.05). However, patients treated with calcitonin significantly reduced pain intensity than those with diclofenac. Moreover, 43.54% of patients in the calcitonin group showed improvement on MRI compared to 21.27% in the diclofenac group, with a significant difference between them (P < 0.05).

Probiotics
To investigate whether probiotic is linked to changes in disability and pain in CLBP patients with MC1 or mixed MCs, 89 patients who met inclusion criteria were enrolled in an RCT conducted by Jensen et al. [37] to receive either probiotics capsule (Lactobacillus Rhamnosis GG) or a placebo capsule twice daily for 100 days. The results showed that although back pain decreased by 1.1 more (95% CI: 0.20-1.97, p ¼ 0.017) in the probiotics group than placebo, no statistically significant differences in primary or secondary outcomes between the two groups were detected. Thus, there was no effect of 100-day treatment with probiotics except for a small, almost clinically insignificant effect on back pain caused by MC1 at 1 year.

Combined physiotherapy with medication
Only one study [38] reported on the efficacy of combined physiotherapy with medication in the treatment of patients with MCs. In this study, 129 patients were allocated to three groups according to the presence or absence of MCs and the type of MCs and all received the functional exercise (McKenzie method) in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants for 6 months. The rates of improvement in ODI scores for CLBP patients with MC1 and MC2 were 57.7% and 48.0%, respectively, and those for VAS scores were 54.7% and 46.0% at three months of treatment. At the treatment endpoint, the ODI and VAS scores for patients with MC1 again improved by 16.1% and 13.8%. However, relevant adverse events did not report in the paper.

Discussion
MCs are the specific imaging manifestations characterized by CLBP as a clinical feature [39]. The underlying mechanism remains unclear and debated (mechanical, local infection, genetic) [40,41,42]. For patients with MCs, the clinical approach remains based on the treatment principles of CLBP, with a focus on reducing pain intensity. As the understanding of MCs has increased, treatment options to address the underlying causes of MCs have been reported but the results are still controversial. To our best knowledge, this is the first systematic review to summarize multiple non-surgical modalities for the treatment of MCs. In this study, we found that 1) The rigid lumbar brace will only improve the patient's clinical symptoms during treatment; 2) Only special subgroups of patients with MCs will benefit in the short term from spinal manipulation (e.g., combined disc herniation) and exercise therapy (e.g., MC1 or larger size of MCs); 3) The rationale and safety of antibiotics for the treatment of MCs remain controversial. 4) ZA and calcitonin have moderate clinical effects in reducing the intensity of CLBP in the short term. However, GS and probiotics have no clear efficacy for such patients.

Non-pharmaceutical treatment
Despite almost all MCs patients accompanied with severe disc degeneration, surgeons rarely pay much more attention to this specific imaging sign. Currently, the mechanism of CLBP caused by MCs remains unclear or uncertain. Patients with MCs are always managed clinically according to the treatment principles of CLBP. Therefore, non-surgical treatments are the most common interventions that patients receive after their first visit.
Non-surgical treatments, such as exercise and spinal manipulation, are as effective as surgery in reducing pain intensity, but at a lower cost and risk of complications [43]. Exercise therapy is widely recommended for the treatment of persistent low back pain [44]. However, given the histological presentation of MCs with microfractures at the endplate, vigorous weight-bearing exercise may inhibit microfracture healing, resulting in MCs patients being less likely to improve with exercise therapy. A study by Jensen et al. [24] published in 2012 confirms this viewpoint, but exercise therapy can still exert a limited clinical effect especially in specific populations such as those with larger MC1.
Patients with MCs often suffer from lumbar instability [16] and the mechanical receptors on the endplate are stimulated during movement to produce pain. The custom-made rigid brace can provide immediate lumbar support and is an acceptable treatment option for patients with MCs [45]. However, it is predictable that its efficacy should not last too long, which is related to the fact that it only provides temporary lumbar support. Spinal manipulation is also a well-established method of managing CLBP. Although the two studies from Annen et al. [28,29] targeted on the different study populations, similar findings suggest that spinal manipulation might be considered as an alternative therapy for patients with MCs.
There are no international guidelines for either exercise or manipulative therapy in the treatment of MCs. Generic or inappropriate physiotherapy prescriptions may be effective for only specific patients, which explains the inconsistent results reported across studies. People with CLBP present as a heterogeneous population which highlights the need to provide individualized treatment approaches. Individual studies using specific treatments are difficult to provide strong evidence for clinical practice, and physiotherapy for MCs is still in the exploratory phase and needs further validation. As such, the present work does not yet provide clear guidance to clinicians in their decision-making.

Pharmaceutical treatment
Low-toxicity anaerobic bacteria can continue to grow and spread to the endplates and their adjacent bone marrow after reaching the intervertebral discs through the blood circulation [46], leading to the occurrence of MCs. This result has been confirmed by previous animal experiments [47]. Considering that one hypothesis is that bacterial infection might be a potential mechanism, antibiotics were adopted experimentally to treat MCs in several studies. Both studies performed by Albert et al. [26,31] revealed that patients with MCs could obtain clinical improvement after antibiotics treatment but with high adverse events. To verify the reliability of the above findings, a replicated randomized multicentre study was recently published in the journal of BMJ [32]. However, the findings from this study have aroused widespread interest and intense debate in academia about the rationale for the antibiotic treatment of MCs.
Although positive bacterial culture results from disc tissue have been reported in several studies [48,49], the similarity of these positive bacteria to colonies existing skin or muscle still cannot rule out the possibility of contamination from other tissues adjacent to the surgical area. Previous studies have not been able to clarify whether MCs are infectious and therefore the use of antibiotics to treat MCs may not be justified. Additionally, the rational use of antibiotics must involve the selection of the right drug, the appropriate dose and duration, and these clinical issues still need to be explored in subsequent high-quality, multicentre studies. Moreover, antibiotic treatment for a large population may also increase the risk of antibiotic resistance [18], which needs to be considered carefully in clinical practice. Instead, the priority should be to clarify the relationship between bacterial infections and MCs, which may be more important than exploring the safety and efficacy of antibiotics in the treatment of such patients.
ZA is a potent bisphosphonate that inhibits osteoblast recruitment, differentiation and function, and promotes apoptosis [50]. Moreover, calcitonin is a potent inhibitor of bone resorption in osteoblasts, primarily for the treatment of osteoporosis and other diseases involving high bone turnover [51]. Considering their pharmacological properties, they have been introduced experimentally in the treatment of MCs. The two studies [34,35] included in the present work that explored ZA and calcitonin for patients with MCs both obtained promising results in the short term.
The pathological process of MCs mainly involves inflammation, high bone turnover, and fibrosis [52]. MC1, which is closely associated with inflammation, is thought to be highly linked to pain, while MC2 and MC3 are reported to be less painful [41]. Not only is the occurrence of CLBP correlated with the stimulation of mechanoreceptors caused by endplate microfracture, but it also leads to the stimulation of chemoreceptors by the release of pro-inflammatory factors [35]. The pharmacological effects of calcitonin in maintaining subchondral and trabecular microstructure and promoting the cartilaginous phase of fracture healing reported in relevant animal studies [53] may be able to explain the findings of Zhou et al. [36] In contrast, ZA, a type of bisphosphonates, inhibits the secretion of pro-inflammatory cytokines such as interleukin 1 (IL-1), TNF-α, and IL-6 [54] and reduces bone marrow edema on MRI [55]. It can be assumed that it exerts its clinical effects by interfering with the pathological process of MCs and accelerating the conversion of MC1 to MC2. However, the pain-causing mechanism of MCs may have consisted of multiple factors or cytokines. Despite the ability of GS to slow the destruction of osteoarthritic cartilage by inhibiting IL-1β [56], patients with MCs failed to benefit from it. This may be able to suggest that IL-1β has little to do with the pathology of MCs or that GS cannot reach the target area due to inadequate blood supply to intervertebral discs and vertebral bodies [33]. Clinical interventions that target the pathological process of MCs may provide new ideas for the treatment of such patients. However, we should still pay much more attention to the adverse events of these drugs, especially in patients with hepatic or renal dysfunction.

Limitations
Similar to other studies, some limitations of the present work should be pointed out. First, present work included multiple managements in the treatment of MCs. However, the results of most interventions were only reported by individual studies, which may reduce the strength of the evidence. Moreover, although we attempt to focus on participants with MCs, it's still unable to control all potential sources of variability among participants. Additionally, due to the different incidence among three types of MCs, most studies have not been able to analyze them separately. In contrast, each of these three types represents a different stage in the pathological process of MCs and they may respond differently to treatment options, allowing for heterogeneity in study results. Finally, this study suffers from publication bias and language bias, as we only included the published paper written in English. Although the exclusion of non-English articles does not usually have a significant impact on the results of systematic reviews [57], we were unable to determine this definitively.

Conclusions
There were several non-surgical interventions used to treat CLBP patients with MCs, with the aim of reducing pain intensity. This systematic review of 15 studies involving MCs patients with clinical results provides limited evidence that patients treated with ZA and calcitonin can achieve short-term symptomatic improvement. However, current findings don't suggest that GS and Probiotics are effective in the treatment of MCs. Exercise and manipulative therapy may only work well for certain patients with MCs. In contrast, the rationale of antibiotic treatment for MCs has not been proven. To sum up, there is not yet enough evidence to suggest that non-surgical treatments are useful for patients with MCs. Further high-quality, multicenter trials are required to validate the effectiveness of these non-surgical treatments.

Data availability statement
Data included in article/supp. material/referenced in article.